Modulation of basal ganglia neurotransmission by the classical antipsychotic fluphenazine is due in part to the blockade of dopamine D 1-receptors

Abstract

Classical antipsychotics, such as fluphenazine, influence neurotransmission by blocking both dopamine D 1- and D 2-receptors which in turn results in widespread adaptive changes in the neurochemistry of the basal ganglia. The purpose of the present study was to determine the role of D 1-receptors in mediating some of these neurochemical events, including changes in D 1- and D 2-receptor binding, and the expression of preproenkephalin and glutamic acid decarboxylase mRNAs. For these experiments, rats were given a depot injection of fluphenazine decanoate or injected twice daily for 21 days with the D 1-receptor antagonist SCH-23390. An additional group received both fluphenazine and SCH-23390 and controls were given saline. Fluphenazine administration decreased D 2-receptor binding throughout the basal ganglia while SCH-23390 was without effect. In contrast to the uniform reduction in D 2-receptor binding, fluphenazine altered D 1-receptor binding in a region-dependent manner. Region-dependent changes were also observed in animals given SCH-23390 which increased binding in the entopeduncular nucleus and posterior caudate-putamen without affecting other brain regions. Both fluphenazine and SCH-23390 significantly enhanced preproenkephalin and glutamic acid decarboxylase (GAD) mRNA expression in the anterior striatum. Fluphenazine also increased GAD mRNA levels in the entopeduncular nucleus. Together, these results indicate that the attenuation of D 1-receptor-mediated neurotransmission modulates a number of clinically relevant neurochemical processes in the basal ganglia.